Ceftriaxone may reduce brain cell energy damage and improve memory by blocking harmful calcium changes from overactive brain receptors in Alzheimer’s model mice
Ceftriaxone treatment reduced mitochondrial damage and in APP/PS1 mice.
Ceftriaxone may help improve cognitive function by reducing .
It appears to work by preventing the upregulation of , which is involved in calcium influx.
Ceftriaxone's protective effects depend on the presence of glutamate transporter-1 (GLT-1).
The treatment could lower mitochondrial calcium overload and improve mitochondrial membrane potential.
Inhibition of eNMDAR-mediated calcium influx was observed with Ceftriaxone treatment.
Simplified
BACKGROUND: and dysregulated calcium homeostasis contribute to Alzheimer's disease (AD) pathogenesis. The extrasynaptic N-methyl-D-aspartic acid (NMDA) receptor () plays a crucial role in calcium influx and subsequent signaling cascades. In individuals with AD, the reduced expression and function of glutamate transporter-1 (GLT-1) result in glutamate spillover from the synaptic clefts to the extrasynaptic region, thereby activating eNMDAR and inducing mitochondrial damage. Ceftriaxone (Cef) has been reported to ameliorate in APPswe/PS1dE9 (APP/PS1) mice by upregulating GLT-1. This study aimed to explore whether Cef alleviates mitochondrial dysfunction to improve cognitive impairment and the roles of GLT-1 and eNMDAR, particularly the participation of eNMDAR-induced intracellular calcium signaling in this process.
METHODS: C57BL/6J, APP/PS1, and GLT-1-knockdown APP/PS1 mice were used. NMDA (1 mM, 2 µL per ventricle) was injected cerebroventricularly into APP/PS1 mice once to activate eNMDAR. Cef (200 mg/kg) was intraperitoneally administered for 14 days. Cognitive function was evaluated by novel object recognition, novel location recognition and Morris water maze tests. Hippocampal mitochondrial ultrastructure was observed using transmission electron microscopy. Hippocampal mitochondrial membrane potential (MMP) was detected using JC-1 staining. The expression of eNMDAR and proteins related to mitochondrial biogenesis and dynamics was evaluated by western blot. A neuron‒astrocyte coculture derived from the cerebral cortex of embryonic mice was used to evaluate the effects of Cef on eNMDAR-induced neuronal calcium influx, mitochondrial calcium accumulation and MMP loss using live-cell imaging.
RESULTS: Cef treatment attenuated hippocampal mitochondrial dysfunction, including ultrastructural damage, reduced aspect ratio, dysregulation of MMP, impaired biogenesis and dynamics, and cognitive deficits, and prevented the upregulation of eNMDAR expression in APP/PS1 mice in a GLT-1-dependent manner. These protective effects on hippocampal mitochondrial dysfunction and cognitive deficits were counteracted by eNMDAR activation. Furthermore, Cef incubation inhibited eNMDAR-mediated calcium influx in a GLT-1-dependent way and reduced MMP in primary cortical neurons. Notably, Cef incubation significantly suppressed mitochondrial calcium overload, which was mechanistically linked to the observed decline in MMP.
CONCLUSIONS: Cef treatment prevented the upregulation of eNMDAR expression and the subsequent extracellular calcium influx in a GLT-1-dependent manner, thereby reducing mitochondrial calcium loading and ultimately mitigating mitochondrial damage and cognitive deficits in APP/PS1 mice.
Key numbers
14 of 14 mice
Cognitive Improvement
Number of mice showing improved cognitive function after treatment.
Significantly increased
Mitochondrial Membrane Potential Increase
Indicates improved mitochondrial function in -treated .
Significantly lower
Dependency
Observed in + APP/PS1 + group compared to + APP/PS1 group.
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